针灸对心肌细胞钙超载保护机制的研究进展

钙离子(Ca~(2+))作为细胞内普遍存在的第二信使,其相关的信号转导通路参与了机体内多种生理活动和病理变化的信号转导,具有广泛和重要的生理学作用,但其具体机制尚未被完全阐明。目前在心肌损伤的机制研究中,钙超载学说已得到医学学术界的公认,越来越多的研究证明钙超载是引发心肌细胞损伤的重要原因之一。笔者查阅了近10年国内外相关的文献资料发现,针灸对心肌细胞钙超载的保护机制主要有细胞膜Ca~(2+)转运途径、肌浆网膜Ca~(2+)转运途径及线粒体途径(即能量代谢途径)等。     

Akt／GSK-3β信号通路和线粒体渗透性转换孔在吸入性麻醉药预处理对老年大鼠心肌缺血保护的研究

目的Akt／GSK．3β信号通路的激活参与了吸人麻醉药心肌保护预处理。在该研究中观察了老年和成年大鼠在异氟醚心肌保护预处理中的差异,包括Akt／GSK-3β信号通路和线粒体渗透性转换孔在异氟醚预处理中的差异。方法雄性Fisher344大鼠按照各自的年龄,成年（3—5月）、老年（20～24月）,随机分配到阴性对照组（sc）、缺血再灌注组（I／R）、异氟醚组（ISO）中。ISO组,大鼠接受30min1．0MAC的异氟醚预处理。I／R组,大鼠接受30min的心肌缺血。方案A中,大鼠接受2h再灌注,用来检测梗死面积。方案B中,大鼠接受10min再灌注,用Westcrn来检测P-Akt,Akt,P—GSK-3β,GSK．3β的表达;并且用分光光度法分析组织中烟酰胺腺嘌呤二核苷酸（NAD＋）水平,作为反映线粒体渗透性转换孔（mPTP）开放的指标。结果成年组大鼠,异氟醚预处理组（YISO＋I／R）心肌梗死面积为29．9％±1．9％,明显低于缺血再灌注组（YI／R,51．8％±2．1％,P〈0．001）。而老年组大鼠,异氟醚预处理失去心肌保护作用（OISO＋I／R--39．9％4-3．7％VSOI／R=46．9％±2．5％,P〉0．05）。比较成年阴性对照组（YSC组）和成年缺血再灌注组（YI／R组）,异氟醚预处理显著提高了成年异氟醚组（YISO组）和成年异氟醚＋缺血再灌注组（YISO＋I／R组）的Akt和GSK-3B的磷酸化水平（P〈0．05）。但是老年组大鼠,Akt和GSK-39磷酸化水平已经在阴性对照组（osc组）提高（对比YSC组）。异氟醚预处理没有进一步提高老年异氟醚组（OISO组）和老年异氟醚＋缺血再灌注组（OISO＋I／R组）的Akt和GSK-3B的磷酸化水平（P〈0．05）。同样,异氟醚预处理减少了成年组大鼠心肌组织中NAD’的减少,而异氟醚预处理失去了对老年组大鼠的NAD＋流失保护作用。结论老年大鼠失去异氟醚预处理心肌保护作用,失去进一步提高Akt、GSK．3β的磷酸化水平能力和失去关闭mPTP是其机理之一。     

Pyruvate/dichloroacetate supply during reperfusion accelerates recovery of cardiac energetics and improves mechanical function following cardioplegic arrest

Objectives: Cardioplegic arrest during cardiac surgery induces severe abnormalities of the pyruvate metabolism, which may affect functional recovery of the heart. We aimed to evaluate the effect of pyruvate and dichloroacetate administration during reperfusion on recovery of mechanical function and energy metabolism in the heart subjected to prolonged cardioplegic arrest. Methods: Four groups of rat hearts perfused in working mode were subjected to cardioplegic arrest (St. Thomas’ No. 1), 4 h of ischaemia at 8°C and reperfusion with either Krebs buffer alone (C) or with 2.8 mM pyruvate (P), with 1 mM dichloroacetate (D), or with a combination of both (PD). Mechanical function was recorded before cardioplegic arrest and at the end of experiments. In groups C and PD, additional experiments were performed using ³¹P nuclear magnetic resonance spectroscopy in non-working Langendorff mode to evaluate cardiac high-energy phosphate concentration changes throughout the experiment. Results: Improved recovery of cardiac output (% of the preischaemic value±SEM, n=9–12) was observed in all three treated groups (65.7±4.3, 59.5±5.2 and 59.5±5.3% in PD, P and D, respectively) as compared with C (42.2±4.6%; P<0.05). Recovery of coronary flow was improved from 66.4±3.8 in C to 94.9±8.6% in PD (P<0.05). The phosphocreatine recovery rate in the first minutes of reperfusion was increased from 9.9±1.5 in C to 31.5±4.3 μmol/min per g dry wt in PD (P<0.001). No differences were observed in ATP or phosphocreatine concentrations at the end of experiment. Conclusions: The administration of pyruvate and dichloroacetate improves the recovery of mechanical function following hypothermic ischaemia. Accelerated restoration of the energy equilibrium in the initial phase of reperfusion may underlie the metabolic mechanism of this effect.     

Disodium Disuccinate Astaxanthin (CardaxTM): Antioxidant and Antiinflammatory Cardioprotection

Disodium disuccinate astaxanthin (Cardax^TM, DDA) has cardioprotective effects in the rat, rabbit, and canine models of experimental infarction. It is highly effective by parenteral administration in subchronic and acute dosing regimens. Unpublished data in rats suggest that oral cardioprotection is also readily achievable. DDA‐induced myocardial salvage in the canine can reach 100% with a 4‐day subchronic dosing regimen. At a single i.v. dose DDA is cardioprotective, when given 2 h before experimental coronary occlusion, but the protection is on the average two‐thirds of that achieved with the subchronic regimen in dogs. In conscious animals DDA has no effects on hemodynamic parameters. The primary mechanism of cardioprotection appears to be antioxidant activity involving direct scavenging of superoxide anion, the lynchpin radical in ischemia‐reperfusion injury. In addition, modulation of serum complement activity, as well as the reduction in the levels of C‐reactive protein (CRP) and the membrane attack complex (MAC) in infarcted tissue suggest a significant antiinflammatory component in the mechanism of cardioprotective action of DDA. Stoichiometric binding of the meso‐form of the compound to human serum albumin (HSA) has been demonstrated in vitro. This binding capacity overcomes the supramolecular assembly of the compound in aqueous solution, which by itself improves the stability and shelf life of aqueous formulations. Non‐esterified astaxanthin readily enters cardiac tissue after either oral or parenteral administration, providing a reservoir of a cardioprotective agent with a significant half‐life due to favorable ADME in mammals. Due to the well‐documented safety profile of non‐esterified astaxanthin in humans, disodium disuccinate astaxanthin may well find clinical utility in cardiovascular indications in humans following successful completion of preclinical and clinical pharmacology and toxicology studies.     

Effects of Chios mastic gum on cardiometabolic risk factors

Chios mastic gum (CMG), the resin produced by the trunk of Pistachia lentiscus var Chia, has been used for culinary and medicinal purposes since antiquity. Despite the fact that Pistacia species are widely distributed throughout the Mediterranean basin and in the circum-Mediterranean regions, CMG is a distinctive resin of the mastic trees grown exclusively in the southern part of the island of Chios. CMG has been used for centuries as a spice, a cosmetic, but its most important usage has been as a strong phytotherapeutic therapy, primarily for the management of gastrointestinal diseases. Recently, there are studies demonstrating that CMG has hypolipidemic, cardioprotective and antidiabetic properties. Therefore, the aim of the present review is to summarize the existing literature data regarding the potential beneficial effects of CMG on cardio-metabolic risk factors.     

Molecular biology of doxorubicin-induced cardiomyopathy

The anthracycline doxorubicin is an antineoplastic agent, eliciting chronic cardiac toxicity. It occurs in patients after prolonged administration of doxorubicin, leading to congestive heart failure. The pathogenesis of the doxorubicin-induced car-diomyopathy is not well understood. The present article summarizes the unique effect of doxorubicin on cardiac-specific gene expression. In addition to binding to DNA, doxorubicin directly affects the function of a variety of proteins. Free radical generation, damage to mitochondria and active cell death are also critical in the development of doxorubicin-induced cardiac toxicity. Agents providing effective cardioprotection are also reviewed.     

浅低温体外循环间断灌注的心肌保护效果观察

探讨浅低温体外循环温血间断灌注心肌保护的临床效果,提高瓣膜置换、冠脉搭桥手术的成功率。方法①浅低温体外循环温血高钾持续灌注心肌保护为对照组(A,n=53);②浅低温体外循环温血高钾间断灌注心肌保护为实验组(B,n=75)。观察两组临床结果并进行比较。结果体外循环时间、主动脉阻断时间B组明显少于A组;库血用量和24h胸腔引流量B组明显少于A组;主动脉开放前血钾浓度B组明显低于A组;主动脉开放后心脏自动复跳率B组明显高于A组。结论浅低温体外循环温血高钾间断灌注保护心肌效果显著,方法简单可行。     

Modulation of myocardial SOD and iNOS during ischemia-reperfusion by antisense directed at ACE mRNA

Renin-angiotensin system (RAS) is involved in the regulation of superoxide dismutase (SOD) and nitric oxide (NO) equilibrium, and its modulation protects hearts from ischemic dysfunction. We examined the effect of a new antisense-oligodeoxynucleotides (AS-ODNs) directed at ACE mRNA on SOD and iNOS expression during myocardial ischemia. Sprague-Dawley rats were treated with saline, AS-ODNs, or inverted-ODNs (IN-ODNs), given with liposome DOTAP/DOPE. Hearts were excised and subjected to 25 min of ischemia followed by 30 min of reperfusion. Ischemia-reperfusion in saline-treated hearts resulted in a decrease in the expression of SOD and an increase in the expression of inducible NOS (iNOS) genes concurrently with myocardial dysfunction. AS-ODNs, but not IN-ODNs, protected hearts against functional deterioration, and upregulated SOD expression and inhibited the expression of iNOS. ACE protein expression was decreased in the rat hearts of the AS-ODNs-treated group, but not in the IN-ODNs group. Thus manipulation of RAS with AS-ODNs directed at ACE mRNA can ameliorate cardiac dysfunction and modulate expression of SOD and iNOS at genomic level.     

Korean Red Ginseng Induced Cardioprotection against Myocardial Ischemia in Guinea Pig

This study was designed to evaluate the protective effect of Korean red ginseng (KRG) against ischemia/reperfusion (I/R) injury in isolated guinea pig heart. KRG has been shown to possess various ginsenosides, which are the major components of Panax ginseng. These components are known naturally occurring compounds with beneficial effects and free radical scavenging activity. The heart was induced to ischemia for 60 min, followed by 120 min reperfusion. The hearts were randomly allocated into five groups (n=8 for each group): normal control (N/C), KRG control, I/R control, 250 mg/kg KRG group and 500 mg/kg KRG group. KRG significantly increased hemodynamics parameters such as aortic flow, coronary flow and cardiac output. Moreover, KRG significantly increased left ventricular systolic pressure (LVSP), the maximal rate of contraction (+dP/dt_max) and maximal rate of relaxation (-dP/dt_max). Also, treatment of KRG ameliorated electrocardiographic index such as the QRS, QT and RR intervals. Moreover, KRG significantly suppressed the lactate dehydrogenase, creatine kinase-MB fraction and cardiac troponin I and ameliorated the oxidative stress markers such as malondialdehyde and glutathione. KRG was standardized through ultra performance liquid chromatograph analysis for its major ginsenosides. Taken together, KRG has been shown to prevent cardiac injury by normalizing the biochemical and oxidative stress.     

Extracts from Astragalus membranaceus limit myocardial cell death and improve cardiac function in a rat model of myocardial ischemia

Ethnopharmacological relevance

The root of Astragalus membranaceus, known as “huang-qi”, is one of the most widely used Chinese herbal medicines for the prevention and treatment of myocardial ischemic diseases. However, the mechanisms governing its therapeutic effects are largely unknown.

Aims of the study

The aims of the present study were to investigate the cardioprotective effect of the root extract of Astragalu membranaceus (EAM) in myocardial ischemia and to explore its underlying mechanisms in ROS-mediated signaling cascade in vivo and in vitro.

Materials and methods

The saponins in EAM were analyzed using HPLC. The tests for the cardioprotective effects of EAM and its mechanisms were performed in vivo and in vitro. In vivo, the rat model of persistent myocardial ischemia was produced by occlusion of the left anterior descending (LAD) coronary artery. In vitro, the cardiomyocyte model of oxidative stress was mimicked by the direct free radical donor, H₂O₂.

Results

In vivo, the increased myocardial infarct size and the increased serum levels of lactate dehydrogenase (LDH), creatine kinase isoform MB (CK-MB), and cardiac troponin (cTnI) were significantly decreased by pre-treatment with EAM. Moreover, cardiac function, as assessed by±dP/dt, left ventricular developed pressure (LVDP), and left ventricular end-diastolic pressure (LVEDP), was dramatically improved. An oxidative stress biomarker, malondialdehyde (MDA), was reduced, and the antioxidant enzyme superoxide dismutase (SOD) was induced. In vitro, H₂O₂-triggered myocardial cell death and cytoplasm Ca²⁺ overload were blocked by treatment with EAM. Furthermore, the K_ATP channel blocker (5-HD, glibenclamide) blocked the anti-apoptotic protective effect of EAM on cardiomyocytes injured by H₂O₂.

Conclusions

The cardioprotection of EAM was manifested as a protection of tissue structure and as a decrease in serum markers of ischemic injury. The mechanisms underlying the EAM-mediated protective effects may involve improving cardiac function, attenuating the oxidative injury via a decrease in MDA, a maintenance in SOD, and a reduction in free radical-induced myocardial cell injury. Additionally, EAM enhanced the myocardial cell viability via arresting the influx of Ca²⁺ to block cell death and opening mitochondrial K_ATP channels to reduce cell apoptosis.